Chemokine receptors are expressed on the surface of certain cells, which interact with cytokines called chemokines. The CXC chemokine receptor 4 (CXCR4) is a G-protein-coupled receptor that transduces signals of its endogenous ligand, the chemokine CXCL12 (stromal cell-derived factor-1, SDF-1). Following interaction of CXCR4/CXCL12 intracellular calcium (Ca2+) ions fluxes are triggered. This causes cellular responses, including chemotaxis allowing cells to travel within the organism. CXCR4 is expressed on myeloid cells, T-lymphocytes, B-lymphocytes, epithelial cells, endothelial cells and dendritic cells. The chemokine CXCL12 is the only known agonistic ligand of CXCR4. The interaction between CXCL12 and CXCR4 plays a crucial role in the migration of progenitor cells during embryologic development of the cardiovascular, hemopoietic or central nervous systems. This interaction is also known to be involved in several diseases such as HIV infection/AIDS, cancer cell metastasis, leukemia cell progression, pulmonary fibrosis and rheumatoid arthritis. It is assumed that this interaction may be a critical therapeutic target in all of these diseases. Substances interfering with CXCR4/CXCL12 signaling are assumed to have drug potential, e.g. in HIV/AIDS therapy, or to prevent cell migration processes involved in cancer metastasis, leukemia, and inflammatory diseases such as pulmonary fibrosis, rheumatoid arthritis or asthma (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289). In contrast to receptor agonists such as CXCL12 that induce cellular responses, receptor antagonists are ligands or drugs that do not induce a biological response, i.e. cell migration or Ca2+ signaling, upon binding to their receptor. Receptor antagonists are useful drugs already in clinical use (e.g. angiotensin antagonists, β-adrenergic antagonists, serotonergic antagonist or CCR5 antagonists) that can block HIV-1 infection (CCR5 antagonist) or decrease agonist mediated cellular responses. Interaction of receptor antagonists with the receptor inhibits the function of an agonist. Most drug antagonists achieve their potency by competing with endogenous ligands or substrates at structurally defined binding sites on receptors.
It has already been shown in vitro and in vivo that CXCR4 antagonists block cancer cell migration and hence metastasis. CXCR4 is expressed on the surface of a variety of cells (myeloid cells, T-lymphocytes, B-lymphocytes, epithelial cells, endothelial cells and dendritic cells) as well as in 23 different types of cancer cells. CXCL12-CXCR4 interaction is involved in metastasis of several types of cancer, including cancer of the breast, kidney, prostate, lung, and pancreas, and melanoma, neuroblastoma, non-Hodgkin's lymphoma, multiple myeloma, ovarian cancer, and malignant brain tumors (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289). It has been shown that CXCR4 antagonists such as T140 analogous suppress CXCL12 induced pancreatic cell migration and invasion or breast carcinoma cell migration in vitro and in vivo (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289). It has also been demonstrated that CXCR4 antagonists effectively suppress invasion and adhesion of small cell lung cancer (SCLC) in vitro (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289), confirming the involvement of the CXCL12-CXCR4 interaction in SCLC metastasis. CXCR4/CXCL12 interaction is also involved in the development of precursor-B (pre-B) acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL. CXCR4 antagonists also attenuate migration of pre-B ALL cells (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289). Furthermore it has been shown that rheumatoid arthritis is caused by CXCR4 expressing CD4+ memory T cell accumulation in the inflamed synovium. CXCL12 concentration in the synovium of rheumatoid arthritis patients are highly elevated thereby attracting memory T cell. CXCR4 antagonistic molecules block migration of memory T cells into the synovium (reviewed in Tsutsumi et al., 2007, Peptide Science 88: 279-289).
CXCR4 antagonists do not only inhibit binding of the agonist CXCL12 to CXCR4 but also prevent interaction of the HIV glycoprotein gp120 with CXCR4 thereby inhibiting virus infection. The human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2) use cell surface expressed CD4 as primary receptor and the chemokine receptors CCR5 or CXCR4 as coreceptors for cell entry. Viruses that infect cells via CD4 and CXCR4 are termed CXCR4 (X4) tropic, HIV-1 variants using CD4 and CCR5 as R5 tropic, and those that can use both coreceptors as dualtropic. X4 tropic HIV-1 variants can only be found in about 50% of all AIDS patients whereas R5 tropic HIV variants predominate in earlier stages and the asymptomatic phase of HIV-1 infection. It has been shown that X4 tropic HIV-1 infection can be blocked in vitro and in HIV-1 infected humans by treating cells or patients with CXCR4 antagonists such as AMD3100. Interestingly, Maraviroc, a CCR5 antagonist, is the first clinical approved drug in AIDS therapy that blocks infection of R5 tropic HIV-1 variants (reviewed by Tsibris and Kuritzkes, 2007, Annual Review of Medicine 58:445-459).
Thus, the chemokine receptor CXCR4 is an attractive therapeutic target for the treatment of HIV/AIDS, cancer associated pathologies and chronic inflammatory diseases like asthma or pulmonary fibrosis. CXCR4 antagonists blocking CXCL12 mediated cellular responses could inhibit these important pathways of disease development and progression.